Acute kidney injury (AKI) is a common disorder with an exceedingly high morbidity and mortality. Both inflammation and direct injury to renal epithelial cells play important roles in the pathogenesis of AKI. Certain endogenous molecules act to limit acute kidney injury. One such molecule is netrin-1 found to be expressed in kidney. However, the mechanisms through which netrin-1 suppresses inflammation and activates cell survival pathways are unknown. The objective of this application is to determine the mechanisms by which activation of signaling pathways by netrin-1 lead to protection of kidney against ischemia reperfusion injury. Netrins are a family of neuronal guidance cues highly expressed in kidney parenchymal cells and their receptors are expressed both in circulating leukocytes and tubular epithelial cells. Our central hypothesis is that netrin-1 protects against ischemic renal injury by inhibiting leukocyte migration and inflammation via the UNC5B receptor expressed on lymphocytes and by activating cell survival pathways in proximal tubular epithelial cells. This hypothesis is based on our extensive preliminary data which clearly indicate that either administration of recombinant netrin-1 or overexpression of netrin-1 in tubular epithelial cells reduced ischemia reperfusion induced kidney injury and reduced inflammation. We plan to test our hypothesis and achieve the objective of this application by pursuing the following three Specific Aims: #1. Determine the mechanism by which netrin-1 reduces inflammation in ischemic AKI. #2. Determine the mechanism by which netrin-1 reduces ischemic epithelial cell injury. #3. Determine the mechanism of regulation of netrin-1 mRNA translation and secretion in proximal tubular epithelial cells during ischemia. The proposed work is innovative because the role of netrin-1 and its receptors in AKI is unknown. Our expectation is that the results will provide novel insights into the mechanisms by which netrin-1 signaling regulates inflammation and epithelial cell survival and subsequent protection from structural and functional damage. It will also reveal new information defining the regulation of netrin-1 production in response to ischemic renal injury. PUBLIC HEALTH RELEVANCE: The proposed studies will elucidate the key role of netrin-1 and its receptor UNC5B in ischemia reperfusion injury of the kidney. They will also define the central role of kidney netrin-1 receptor signaling in regulating migration of inflammatory cells infiltrate into kidney and mechanism of netrin-1 mediated suppression apoptosis in renal epithelial cells. These results will be relevant because they are expected to lead to clinical trials to test the efficacy of recombinant netrin-1 and other signaling pathway inhibitors for the prevention or treatment of acute renal injury.